Corticotropin Releasing Factor (CRF) was a peptide comprising 41 amino acid residues and isolated from ovine hypothalamic in 1981. It was suggested that CRF was released from hypothalamic and controlled a secretion of adrenocorticotropic hormone (ACTH) from hypophysis [Science, 218, 377-379 (1982)].
A biological effect is begun from CRF binds to CRF receptor, which exists on membranous surface of ACTH producing cell in anterior pituitary. Two subtypes of CRF receptors have been identified, and each one of these is distributed in a different area of brain. For example, a lot of receptor 1 is distributed in hypophysis, hypothalamic, cerebral cortex and a lot of receptor 2 is distributed in septal of brain, hypothalamus nucleus paraventricularis. Besides, receptors are also distributed in peripheral organ, for example, heart, gastrointestinal, lung, adrenal medulla, spleen, liver, renal, glandula prostatica. Concretely, receptor 1 is existed in bowel or spleen, receptor 2 is existed in stomach and especially receptor 2β is existed in heart and skeletal muscle.
ACTH, which is released by a stimulation of CRF, stimulates a secretion of cortisol from adrenal cortex, and relates to a systemic action for reproduction, growth, gastrointestinal function, inflammation, immune system, nervous system etc. Consequently, CRF is believed to plays a role as a regulator of these functions.
It was reported that excess CRF was secreted in brain of patient with depression and anxiety disorders [Science, 226, 1342-1343 (1984); Neuroscience and Behavioral Reviews, 22, 635-651 (1998); J. Endocrinol, 160, 1-12 (1999)].
Besides, a relation of CRF and various disorders was reported, for example, eating disorder [Science, 273, 1561-1564 (1996)], inflammation [Endocrinology, 137, 5747-5750 (1996)], irritable bowel syndrome [Am. J. Physiol, 253, G582-G586 (1987)], drug dependence [Psychopharmacology 137, 184-190 (1998)] and ischemia [Soc Neurosci Abstr (November 4-9, New Orleans), 807.5 (2000)].
On the other hand, CRF has an intimate involvement in stress. For example, administration of CRF to the brain elicited same behavior and endocrine response as an animal under stressful conditions [Nature, 297, 331 (1982)].
As above, a relationship of CRF and a disorder of central nerve system, neuropsychiatric disorder or a disorder of peripheral organ has been attracted attention.
Accordingly, an antagonism of CRF receptor is considered to be useful for a disease by abnormal secretion of CRF, for example, various diseases comprising stress-related disorders. For examples, it is believed to be useful for a prevention and/or treatment of depression, single episode depression, recurrent depression, postpartum depression, child abuse induced depression, anxiety, anxiety related disorders (e.g. panic disorder, particular phobia, fear of falling, social phobia, obsessive compulsive disorder), emotional disorder, bipolar disorder, posttraumatic stress disorder, peptic ulcer, diarrhea, constipation, irritable bowl syndrome, inflammatory bowel disease (ulcerative colitis, Crohn's disease), stress-induced gastrointestinal disturbance, nervous emesis, eating disorder (e.g. anorexia nervosa, bulimia nervosa), obesity, stress-induced sleep disorder, pain of muscular fiber induced sleep disorder, stress-induced immune suppression, stress-induced headache, stress-induced fever, stress-induced pain, post operative stress, rheumatoid arthritis, osteoarthritis, osteoporosis, psoriasis, thyroid dysfunction, uveitis, asthma, inappropriate anti-diarrhea hormone induced disorder, pain, inflammation, allergic disease, head injury, spinal cord injury, ischemic neuron injury, toxicity neuron injury, Cushing's disease, seizure, spasm, muscular spasm, epilepsy, ischemic disease, Parkinson's disease, Huntington disease, urinary incontinence, Alzheimer's disease, senile dementia of Alzheimer type, multi-infarct dementia, amyotrophic lateral sclerosis, hypoglycemia, cardiovascular or heart-related disease (hypertension, tachycardia, congestive heart failure), drug addiction or alcohol dependence syndrome.
On the other hand, following compounds having an antagonism activity of CRF were known.
(1) In a specification of WO 97/29109, a compound of formula (A)
wherein    R1A is NR4AR5A or OR5A;    R2A is alkyl, alkyloxy, alkylthio:    R3A is H, alkyl, alkylsulfonyl, alkylsufoxy or alkylthio;    R4A is H, alkyl, mono- or di(cycloalkyl)methyl, cycloalkyl, alkenyl, hydroxyalkyl, alkylcarbonyloxyalkyl or alkyloxyalkyl;    R5A is alkyl, mono- or di(cycloalkyl)methyl, Ar1A—CH2, alkenyl, alkyloxyalkyl, hydroxyalkyl, thienylmethyl, furanylmethyl, alkylthioalkyl, morpholinyl etc.;    or R4A and R5A taken together with the nitrogen atom to which they are attached may form a pyrrolidinyl, piperidinyl, homopiperidinyl or morpholinyl, optionally substituted with alkyl, alkyloxyalkyl;    ArA is phenyl, phenyl substituted with 1, 2 or 3 substitutes independently selected from halo, alkyl, trifluoromethyl, hydroxy, etc.; pyridinyl, pyridinyl substituted with 1, 2 or 3 substitutes independently selected from halo, alkyl, trifluoromethyl, hydroxy; was described as CRF receptor antagonist.(2) In a specification of WO 98/03510, a compound of formula (B)
wherein    AB is N or CRB;    ZB is N or CR2B;    ArB is selected from phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, benzothienyl, benzofuranyl, etc., each ArB optionally substituted with 1 to 5 R4B;    RB is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, halo, cyano or haloalkyl;    R1B is H, alkyl, alkenyl, alkynyl, halo, cyano or haloalkyl, hydroxyalkyl, etc.;    R2B is H, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, etc.;    R3B is H, OR7B, SH, S(O)nR13B, COR7B, CO2R7B, OC(O)R13B, NR8BCOR7B, N(COR7B)2, NR8BCONR6BR7B, NR8BCO2R13B, NR6BR7B, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, etc.;    R4B is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, NO2, halo, cyano, haloalkyl, NR6BR7B, NR8BCOR7B, etc.;was described as CRF receptor antagonist.(3) In a specification of WO 98/08847, a compound of formula (C)
wherein the dashed lines is optional double bonds;    AC is nitrogen or CR7C;    BC is NR1CR2C, CR1CR2CR10C, C(═CR2CR11C)R1C, NHCR1CR2CR10C, OCR1CR2CR10C, SCR1CR2CR10C, CR2CR10CNHR1C, CR2CR10COR1C, CR2CR10CSR1C or COR2C;    JC and KC are each independently nitrogen or carbon and both are not nitrogens;    DC and EC are each selected, independently, from nitrogen, CR4C, C═O, C═S, sulfur, oxygen, CR4CR6C and NR8C;    GC is nitrogen or carbon;    The ring containing DC, EC, GC, KC and JC may be a saturated or unsaturated 5-membered ring and optionally substituted with one or two double bonds and may optionally contain from one to three heteroatoms in the ring and may optionally have one or two C═O or C═S;    R1C is alkyl optionally substituted with one or two substitutes independently selected from hydroxy, fluoro, chloro, bromo, iodo, O-alkyl, CF3, C(═O)O-alkyl, OC(═O)alkyl, etc.;    R2C is alkyl, which may optionally contain from one to three double or triple bonds, aryl or arylalkyl, cycloalkyl, cycloalkylalkyl, etc.;    R3C is H, alkyl, O-alkyl, chloro, fluoro, bromo, iodo, alkylene-O-alkyl, alkylene-OH or S-alkyl;    R4C is H, alkyl, fluoro, chloro, bromo, iodo, hydroxy, cyano, amino, alkylene-OH, CF3, etc;    R5C is phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl and each group is substituted with from one to four substitutes R13C, wherein one to three of said substitutes may be selected, independently, from fluoro, chloro, alkyl and O-alkyl, and one of said substitutes may be selected from bromo, iodo, formyl, OH, alkylene-OH, alkylene-O-alkyl, cyano, CF3, nitro, amino, alkylamino, dialkylamino, etc.;was described as CRF receptor antagonist.